Memantine hydrochloride, 1-amino-3,5-dimethyladamantane hydrochloride, is one of a small group of tricyclic antiviral drugs (TAV). Memantine also provides good and persistent activation of central nervous N-methyl-D-aspartate (NMDA) receptors, and, thus, can be used in the treatment of Parkinson's disease and Alzheimer's disease. There is increasing evidence that memory loss and dementia in Alzheimer's disease are related to malfunctioning of the signals that pass messages between the nerve cells in the brain. In particular, the excessive activity of a chemical called glutamate contributes to the symptoms of Alzheimer's, as well as the progression of this disease. Glutamate acts on the NMDA receptors that are found on nerve cells in the brain. These receptors and nerve cells are involved in transmitting nerve messages in the brain that are important in learning and memory. Reportedly, Glutamate damages the nerve cells by excessively stimulating the NMDA receptors. Memantine works by blocking the NMDA receptors in the brain, blocking the excessive activity of glutamate, but allowing the normal activation of the NMDA receptors that occurs when the brain forms a memory. Memantine may therefore improve brain functioning in Alzheimer's disease, and may also block the glutamate activity that could cause further damage to the brain cells. Memantine is licensed to treat moderately severe to severe Alzheimer's disease. Studies have demonstrated that memantine causes a small improvement or stabilization in the cognitive functioning, i.e., thinking, learning, and memory, and the daily functioning of Alzheimer's patients.
The chemical structure of memantine hydrochloride may be represented by:

There is no known prior art disclosure of polymorphism in memantine hydrochloride. Examples of the crystallization of memantine hydrochloride are reported in a few patents, but none of the patents disclose any polymorphic forms. For example, U.S. Pat. No. 3,391,142 discloses the precipitation of memantine hydrochloride from an anhydrous ether solution and crystallization of the crude product in an alcohol-ether mixture. U.S. Pat. No. 4,122,193 discloses the precipitation of memantine hydrochloride precipitation by bubbling hydrochloric acid in an ether solution of memantine free base, and CZ 282398 discloses adding aqueous hydrochloric acid to toluenic solution of memantine free base to provide the hydrochloride. All prior art methods for the preparation of memantine hydrochloride result in the formation of a single crystalline form, herein Form I, characterized by X-ray diffraction (XRD) having peaks at about: 6.3, 12.5, and 18.8±0.2 degrees 2 theta, and further characterized by peaks at about 11.0, 14.2, 16.6, 21.8, 22.7, 24.4, and 27.4±0.2 degrees 2 theta.
The present invention relates to the solid state physical properties of memantine hydrochloride. These properties can be influenced by controlling the conditions under which memantine hydrochloride is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. The polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC), and can be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography, solid state 13C NMR spectrometry, and infrared spectrometry.
Thus, the discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist as available for designing, for example, a pharmaceutical dosage form of a drug with targeted release profile or other desired characteristic. There is a need in the art for additional crystalline forms of memantine hydrochloride.